The overall goal of this project is to understand the cellular mechanisms by which the neurotrophin, brain derived neurotrophic factor (BDNF) and its high affinity receptor, trk B, regulate neuronal survival, growth and plasticity in the hippocampus. The hippocampus is a brain region intimately linked to the process of learning and memory formation. In addition, certain hippocampal neurons are particularly susceptible to the neurodegeneration that occurs in Alzheimer's disease, stroke, and epilepsy. Neurotrophins, acting through high affinity receptors, are neural growth factors which may protect nerve cells from injury in many neurodegenerative diseases. However, our understanding of the function of the trk B neurotrophin receptor in hippocampal cell development and the neural events modulating its expression is far from complete. Several studies are proposed to investigate the cellular signals which regulate trk B gene and protein expression in the hippocampus. First, the role of trk B in hippocampal cell survival and development in vitro and in vivo will be studied by blocking its production through the use of antisense oligodeoxynucleotide (ODN) technology. In hippocampal cultures, the effect of antisense trk B ODNs on natural cell survival and neuron viability when exposed to insults such as glutamate neurotoxicity and glucose deprivation will be examined. In neonatal rat pups antisense ODN treatment will be evaluated in reference to hippocampal cell density and the immunocytochemical analysis of proteins important in neural development, such as tau, MAP2, and synaptophysin. In a second line of investigation we will examine the effects of activity-related cellular signals on trk B mRNA and protein expression in culture. This will be performed by pharmacologically manipulating impulse activity in cultured hippocampal neurons and determining trk B expression by Northern Blots, RNAse protection assays, and Western Blot analysis. In a similar manner we will explore the role of BDNF as an autoregulator of the levels of its preferred receptor. Preliminary evidence suggests that neural activity and BDNF upregulate trk B protein levels in hippocampal cultures. The proposed studies will enhance our understanding of BDNF and trk B receptor function in hippocampal development and pertinent cellular signaling events regulating trk B expression. This information may elucidate potential therapeutic mechanisms by which the neurotrophin BDNF and its high affinity receptor ameliorate neurodegeneration.